We wish to understand the response of human cells to treatment with mutagenic and carcinogenic agents. How does the genome react with chemical agents, what is the response of the cell to the reaction products, what is the mechanism of the mutation process, what is the relationship between the processes of mutagesis and carcinogenesis? Since the initial events in the carcinogenesis and mutagenesis result from abnormal DNA replication in the presence of lesions not removed by excision repair, we wish to understand the mechanisms and the interactions of these processes in human lymphoblastoid cells and, if possible, to identify the "error-prone" step. In the next year we therefore propose to: 1) Determine whether replication repair in excision deficient cells occurs by branch migration by experiments designed to trap the repair intermediate in xeroderma cells deficient in the excision repair mechanism. 2) Utilize the properties of BND-cellulose to isolate DNA fragments with single stranded regions after treatment of cells with mutagenic agents since such DNA fragments are likely to be intermediates in both post replication repair and degradation processes. 3) Determine the relationship between cell differentiation and excision repair ability in order to understand the sensitivity of some tissues to chemical carcinogens. 4) Relate the observation that repair induced by methyl nitronitrosoguanidine occurs to a greater extent at DNA growing point regions to the observation that this compound is more mutagenic at DNA growing points. BIBLIOGRAPHIC REFERENCES: Strauss, B., 1976. Repair of DNA Adducts Produced by Alkylation, In Aging, Carcinogenesis and Radiation Biology: The Role of Nucleic Acid Addition Reactions (K. Smith, ed.) Plenum Press, New York, pp. 287-314. Scudiero, D. and Strauss, B. 1976. Increased repair in DNA growing point regions after treatment of human lymphoma cells with N-methyl-N'-nitro-N-nitrosoguanidine. Mutation Research, 35: 311-324.